Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer

Chappuis, Pierre O.; Nethercot, Victoria; Foulkes, William D.

doi:10.1002/(sici)1098-2388(200006)18:4<287::aid-ssu3>3.0.co;2-5

Cited by 134 publications

(73 citation statements)

References 97 publications

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“…34 The importance of p53 inactivation in BRCAassociated tumors is also demonstrated by genetic studies in which p53 mutations were present at higher frequencies and in unusual locations in this group compared with sporadic cases. [55][56][57] In a review of reported cases by Chappuis et al, 30 around 40% of BRCA1 and 30% of BRCA2 carcinomas had p53 mutations, whereas only 20% of sporadic controls had them. However, p53 mutations were not found in BRCA2 tumors in one series.…”

Section: P53 Expression and Gene Mutationsmentioning

confidence: 99%

“…[26][27][28][29] Invasive ductal carcinoma-not otherwise specified is the most common histological type in all forms of hereditary breast cancer and seems to be significantly more frequent in BRCA1-and BRCA2-mutation carriers than in noncarriers. 30 In addition, BRCA1-mutation carriers have a higher incidence of medullary carcinoma (13%) than BRCA2-mutation carriers (3%) and noncarriers (2%). 27 When only invasive ductal carcinomas are compared, after excluding medullary carcinomas, BRCA1 tumors more frequently have a prominent lymphocytic infiltrate, foci of necrosis and pushing margins, 26 which are some of the features that define the medullary histotype ( Figure 1).…”

Section: Familial Breast Cancer Characteristicsmentioning

confidence: 99%

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The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

2005

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Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of highgrade, highly proliferating, estrogen receptor-and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor-and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma. Keywords: hereditary breast cancer; BRCA1; BRCA2; molecular pathology; histopathology; immunohistochemistry It is currently estimated that 5-10% of all breast cancers are hereditary and attributable to mutations in high-penetrance susceptibility genes, but only two of these have been identified: BRCA1 (OMIM 113705) 1 and BRCA2 (OMIM 600185). 2 BRCA1 mutations are associated with families with breast and ovarian cancer, while families with male breast tumors are associated with mutations in the BRCA2 gene.While early estimates suggested that BRCA1 and BRCA2 mutations were responsible for 75% of multiple-case breast cancer families and for the majority of families with multiple breast and ovarian cancers, 3,4 recent data have shown that these percentages may have been overestimated. In fact, the percentage of high-risk families associated with mutations in these genes seems to be around 25% in all series investigated, including the Spanish population. 5 Mutations are found in a high percentage (about 45%) of families with breast and ovarian tumors, while the mutation rate in families with only breast can...

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Section: P53 Expression and Gene Mutationsmentioning

confidence: 99%

Section: Familial Breast Cancer Characteristicsmentioning

confidence: 99%

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

2005

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“…The products of two tumour suppressor genes, BRCA1 and WRN, have roles in decatenation checkpoint function, and mutations in either gene may increase the likelihood of cancer in part because of the checkpoint deficiency. Aneuploidy is a common feature of BRCA1-associated cancers (Chappuis et al, 2000). Checkpoint deficiency that is acquired during carcinogenesis, for example in the lung and bladder cancer cell lines described above, may result in additional genetic changes that contribute to tumour progression ( Figure 1C).…”

Section: The Decatenation Checkpoint and Cancermentioning

confidence: 99%

The decatenation checkpoint

Damelin

Bestor

2007

Br J Cancer

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The decatenation checkpoint delays entry into mitosis until the chromosomes have been disentangled. Deficiency in or bypass of the decatenation checkpoint can cause chromosome breakage and nondisjunction during mitosis, which results in aneuploidy and chromosome rearrangements in the daughter cells. A deficiency in the decatenation checkpoint has been reported in lung and bladder cancer cell lines and may contribute to the accumulation of chromosome aberrations that commonly occur during tumour progression. A checkpoint deficiency has also been documented in cultured stem and progenitor cells, and cancer stem cells are likely to be derived from stem and progenitor cells that lack an effective decatenation checkpoint. An inefficient decatenation checkpoint is likely to be a source of the chromosome aberrations that are common features of most tumours, but an inefficient decatenation checkpoint in cancer stem cells could also provide a potential target for chemotherapy.

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“…In most breast cancers arising in BRCA1/2 carriers, inactivation of the wild-type allele has occurred by means of loss of heterozygosity, thus abolishing normal protein expression (Smith et al, 1992;Collins et al, 1995). BRCA1 tumors show a rather uniform tumor type of high-grade invasive ductal carcinomas, which are usually estrogen receptor (ER) and HER2/neu negative (Chappuis et al, 2000;Phillips, 2000). These properties are reminiscent of 'triple-negative' (ER-, progesterone receptor (PR)-and HER2/neu-negative) basal-like sporadic breast cancers (Livasy et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

2006

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Germline mutations in BRCA1 and BRCA2 are responsible for a large proportion of hereditary breast and ovarian cancers. Soon after the identification of both genes in the mid-1990s, investigators set out to develop mouse models for the associated disease. Whereas conventional Brca1 and Brca2 mouse mutants did not reveal a strong phenotype in a heterozygous setting, most homozygous mutations caused embryonic lethality. Consequently, development of mouse models for BRCAassociated tumorigenesis required the generation of tissuespecific conditional knockout animals. In this review, we give an overview of the conventional and the conditional mouse models of BRCA1 and BRCA2 deficiency generated over the last decade, as well as the contribution of these models to our understanding of the biological and molecular functions of BRCA1 and BRCA2. The most advanced mouse models for BRCA1-and BRCA2-associated tumorigenesis mimic human disease to the extent that they can be used in studies addressing clinically relevant questions. These models will help to resolve yet unanswered questions and to translate our increasing knowledge of BRCA1 and BRCA2 biology into clinical practice.

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Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer

Cited by 134 publications

References 97 publications

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

The decatenation checkpoint

Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

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